1. Technical Field of the Invention
The present invention relates to pharmaceutical compositions, and especially dermatological compositions, for treating skin conditions, and especially for treating rosacea (formerly known as acne rosacea). In particular, this invention relates to pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family and azelaic acid.
The present invention also relates to pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least ivermectin and azelaic acid. The invention also relates to the administration of such compositions as medicaments for treating skin conditions, disorders or afflictions, in particular rosacea.
2. Description of Background and/or Related and/or Prior Art
Rosacea is a chronic inflammatory dermatitis that mainly affects the median part of the face and the eyelids of certain adults. It is characterized by telangiectatic erythema, dryness of the skin, papules and pustules.
Conventionally, rosacea develops in adults from the ages of 30 to 50; it more frequently affects women, although the condition is generally more severe in men.
Despite its former name, acne rosacea is not a condition of the pilosebaceous follicles like juvenile acne, but a primitively vascular condition whose inflammatory stage lacks the cysts and comedones characteristic of common acne.
The aetiology of rosacea is still poorly understood, although many theories have been advanced. The most common hypothesis is based on the characteristic presence of the parasite Demodex folliculorum in the case of patients suffering from rosacea. This organism is absent in common acne. Other factors have been described as possibly contributing towards the development of rosacea, such as hormonal factors and especially endocrine factors, climatic and immunological factors, and bacterial factors via the presence of Helicobacter pylori, a bacterium associated with gastrointestinal disorders.
Rosacea develops in four stages over several years, in spasms aggravated by variations in temperature, alcohol, spices, exposure to sunlight and emotions. The various stages of the disease are the following:
Stage 1: stage of erythema episodes. The patients have erythrosis spasms due to the sudden dilation of the arterioles of the face, which then take on a congestive, red appearance. These spasms are caused by the emotions, meals and temperature changes.
Stage 2: stage of couperosis, i.e., of permanent erythema with telangiectasia. Certain patients also have oedema on the cheeks and the forehead.
Stage 3: inflammatory stage with appearance of inflammatory papules and pustules, but without affecting the sebaceous follicles and thus with absence of cysts and comedones.
Stage 4: rhinophyma stage. This late phase essentially affects men. The patients exhibit a bumpy, voluminous red nose with sebaceous hyperplasia and fibrous reordering of the connective tissue.
Conventionally, rosacea is treated orally or topically with antibiotics such as tetracyclines, erythromycin, clindamycin or metronidazole, but also with vitamin A, salicylic acid, anti-fungal agents, steroids, anti-infectious agents such as benzoyl peroxide, with isotretinoin or with azelaic acid.
Azelaic acid (or 1,7-heptanedicarboxylic acid) is known in the prior art for its anti-acne and keratolytic properties. Azelaic acid shows anti-bacterial activity on P. acnes and S. epidermidis. It inhibits keratinocyte proliferation, reduces the level of free fatty acid in sebaceous secretions and also has anti-inflammatory activity.
WO 2004/022 046 describes a method for treating rosacea via topical application of a composition based on azelaic acid and metronidazole.
U.S. Pat. No. 5,952,372 also describes a method for treating rosacea using ivermectin orally or topically in order to reduce and eliminate the parasite Demodex folliculorum present on the skin of patients.
Ivermectin belongs to the avermectin family, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale. The Extra Pharmacopoeia. 29th Edition. Pharmaceutical Press, London). The avermectins especially include ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin.
Ivermectin is known in the prior art for its anti-parasitic and anthelmintic properties. The anti-parasitic activity is thought to be due to the opening of a chlorine channel in the membrane of the neurons of the parasite under the effect of an increased release of the neuromediator GABA (gamma-aminobutyric acid), inducing neuromuscular paralysis that may lead to the death of certain parasites. Ivermectin also interacts with other chlorine channels, especially those dependent on the neuromediator GABA (gamma-aminobutyric acid). It is already described in man in the treatment of onchocercosis caused by Onchocerca volvulus, gastrointestinal strongyloidosis (anguillulosis) (product Stromectol®), human scabies (Meinking T. L. et al., N. Engl. J. Med. 1995, Jul. 6; 333 (1): 26-30 The treatment of scabies with ivermectin) and also in the treatment of diagnosed or suspected microfilaraemia in the case of individuals suffering from lymphatic filariasis caused by Wuchereria bancrofti. 
U.S. Pat. No. 6,133,310 describes the administration of ivermectin in the treatment of rosacea in order to reduce and eliminate the parasite Demodex folliculorum present on the skin of patients.
However, these treatments have drawbacks such as irritation and intolerance phenomena, especially when they are administered for a prolonged period. Furthermore, these treatments are only suppressive and not curative, acting especially on the pustulous spasms occurring during the inflammatory stage.
Considering the chronic nature of rosacea, the ideal treatment requires prolonged use, in a safe and effective manner. Taking the foregoing into account, there is thus a need for a composition that shows improved efficacy in the treatment of rosacea and that does not exhibit the side effects described in the prior art. There is especially a need to formulate a composition that imparts greater tolerance to the active principles, while at the same time reducing their side effects.